Bottom Line:
The TCR is composed of four distinct signal transducing subunits (CD3-gamma, -delta, -epsilon, and zeta) that contain either one (CD3-gamma, -delta, -epsilon) or three (-zeta) signaling motifs (ITAMs) within their intracytoplasmic domains.A possible function for multiple TCR ITAMs could be to amplify signals generated by the TCR during selection.A direct relationship was observed between the number of zeta chain ITAMs within the TCR complex and the efficiency of both positive and negative selection.

ABSTRACTImmature thymocytes undergo a selection process within the thymus based on their T cell antigen receptor (TCR) specificity that results either in their maturation into functionally competent, self-MHC-restricted T cells (positive selection) or their deletion (negative selection). The outcome of thymocyte selection is thought to be controlled by signals transduced by the TCR that vary in relation to the avidity of the TCR-ligand interaction. The TCR is composed of four distinct signal transducing subunits (CD3-gamma, -delta, -epsilon, and zeta) that contain either one (CD3-gamma, -delta, -epsilon) or three (-zeta) signaling motifs (ITAMs) within their intracytoplasmic domains. A possible function for multiple TCR ITAMs could be to amplify signals generated by the TCR during selection. To determine the importance of the multiple TCR-zeta chain ITAMs in thymocyte selection, transgenes encoding alpha/beta TCRs with known specificity were bred into mice in which zeta chains lacking one or more ITAMs had been genetically substituted for endogenous zeta. A direct relationship was observed between the number of zeta chain ITAMs within the TCR complex and the efficiency of both positive and negative selection. These results reveal a role for multiple TCR ITAMs in thymocyte selection and identify a function for TCR signal amplification in formation of the T cell repertoire.

Mentions:
Reconstitution of ζ−/− mice with a transgene encoding a ζ variant chain lacking all three ζ chain ITAMs (ζ-0 ITAM) restores TCR surface expression and promotes the generation of large numbers of CD4+CD8− and CD4−CD8+ SP thymocytes and peripheral T cells (15). Significantly, the T cells generated in ζ-0 ITAM Tg mice are functionally competent as assessed by their ability to respond to TCR-dependent stimuli (Fig. 1; 23). These results demonstrate that TCR-ζ chain signals are not specifically required for either the generation or activation of mature T cells.

Mentions:
Reconstitution of ζ−/− mice with a transgene encoding a ζ variant chain lacking all three ζ chain ITAMs (ζ-0 ITAM) restores TCR surface expression and promotes the generation of large numbers of CD4+CD8− and CD4−CD8+ SP thymocytes and peripheral T cells (15). Significantly, the T cells generated in ζ-0 ITAM Tg mice are functionally competent as assessed by their ability to respond to TCR-dependent stimuli (Fig. 1; 23). These results demonstrate that TCR-ζ chain signals are not specifically required for either the generation or activation of mature T cells.

Bottom Line:
The TCR is composed of four distinct signal transducing subunits (CD3-gamma, -delta, -epsilon, and zeta) that contain either one (CD3-gamma, -delta, -epsilon) or three (-zeta) signaling motifs (ITAMs) within their intracytoplasmic domains.A possible function for multiple TCR ITAMs could be to amplify signals generated by the TCR during selection.A direct relationship was observed between the number of zeta chain ITAMs within the TCR complex and the efficiency of both positive and negative selection.

ABSTRACTImmature thymocytes undergo a selection process within the thymus based on their T cell antigen receptor (TCR) specificity that results either in their maturation into functionally competent, self-MHC-restricted T cells (positive selection) or their deletion (negative selection). The outcome of thymocyte selection is thought to be controlled by signals transduced by the TCR that vary in relation to the avidity of the TCR-ligand interaction. The TCR is composed of four distinct signal transducing subunits (CD3-gamma, -delta, -epsilon, and zeta) that contain either one (CD3-gamma, -delta, -epsilon) or three (-zeta) signaling motifs (ITAMs) within their intracytoplasmic domains. A possible function for multiple TCR ITAMs could be to amplify signals generated by the TCR during selection. To determine the importance of the multiple TCR-zeta chain ITAMs in thymocyte selection, transgenes encoding alpha/beta TCRs with known specificity were bred into mice in which zeta chains lacking one or more ITAMs had been genetically substituted for endogenous zeta. A direct relationship was observed between the number of zeta chain ITAMs within the TCR complex and the efficiency of both positive and negative selection. These results reveal a role for multiple TCR ITAMs in thymocyte selection and identify a function for TCR signal amplification in formation of the T cell repertoire.